Molecular embryology for an understanding of congenital heart diseases

Yamagishi, Hiroyuki; Maeda, Jun; Uchida, Keiko; Tsuchihashi, Takatoshi; Nakazawa, M.; Aramaki, Megumi; Kodo, Kazuki; Yamagishi, Chihiro

doi:10.1007/s12565-009-0023-4

Cited by 16 publications

(11 citation statements)

References 30 publications

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“…Persistent truncus arteriosus (PTA) is the most severe phenotype of outflow tract (OFT) defects, with an unfavorable prognosis as surgical repair is not always possible (Williams et al, 1999). Although discovering the genetic causes would provide insight into the pathogenesis of CHD, the etiology of most human CHD, including OFT defects, remains unknown because of the multifactorial nature of the diseases, indicating the need for more study (Bruneau, 2008;Olson, 2006;Yamagishi et al, 2009;Zhao and Srivastava, 2007).…”

Section: Introductionmentioning

confidence: 99%

Bmp signaling repressesVegfato promote outflow tract cushion development

et al. 2013

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SUMMARYCongenital heart disease (CHD) is a devastating anomaly that affects ~1% of live births. Defects of the outflow tract (OFT) make up a large percentage of human CHD. We investigated Bmp signaling in mouse OFT development by conditionally deleting both Bmp4 and Bmp7 in the second heart field (SHF). SHF Bmp4/7 deficiency resulted in defective epithelial to mesenchymal transition (EMT) and reduced cardiac neural crest ingress, with resultant persistent truncus arteriosus. Using a candidate gene approach, we found that Vegfa was upregulated in the Bmp4/7 mutant hearts. To determine if Vegfa is a downstream Bmp effector during EMT, we examined whether Vegfa is transcriptionally regulated by the Bmp receptor-regulated Smad. Our findings indicate that Smad directly binds to Vegfa chromatin and represses Vegfa transcriptional activity. We also found that Vegfa is a direct target for the miR-17-92 cluster, which is also regulated by Bmp signaling in the SHF. Deletion of miR-17-92 reveals similar phenotypes to Bmp4/7 SHF deletion. To directly address the function of Vegfa repression in Bmp-mediated EMT, we performed ex vivo explant cultures from Bmp4/7 and miR-17-92 mutant hearts. EMT was defective in explants from the Bmp4/7 double conditional knockout (dCKO; Mef2c-Cre;Bmp4/7 f/f ) and miR-17-92 null. By antagonizing Vegfa activity in explants, EMT was rescued in Bmp4/7 dCKO and miR-17-92 null culture. Moreover, overexpression of miR-17-92 partially suppressed the EMT defect in Bmp4/7 mutant embryos. Our study reveals that Vegfa levels in the OFT are tightly controlled by Smad-and microRNA-dependent pathways to modulate OFT development.

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Section: Introductionmentioning

confidence: 99%

Bmp signaling repressesVegfato promote outflow tract cushion development

et al. 2013

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“…7 Commonly, the clinical phenotype of individuals with GATA6 mutations involves the OFT, but is distinct from that of DiGeorge/22q11.2 deletion syndrome and, rather, manifests as non-syndromic CHD. To date, no molecular link has been demonstrated between GATA6 and TBX1, 8,9 however, a recent study showed that the expression of Sema3c in the OFT was downregulated in mouse embryos deficient for Tbx1, 10 suggesting that GATA6 may share, at least in part, a common molecular pathway with TBX1 during OFT development.…”

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confidence: 99%

GATA transcription factors in congenital heart defects: A Commentary on a novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

Kodo

Yamagishi

2010

J Hum Genet

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C ongenital heart defects (CHDs) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. In addition, about 3 per every 1000 live births will require some intervention during the first year of life. 1 Despite its clinical importance, the underlying genetic etiology of most CHD remains unknown. Previous studies succeeded in revealing genetic causes of some syndromic or familial CHD, however, there are limited numbers of such cases, and it is still difficult to approach the etiology of the majority of CHD, that manifest non-syndromic and non-familial phenotype, because of their multi-factorial nature.In this issue, Lin et al. report on a novel mutation of a gene encoding a transcription factor, GATA6, as a possible cause of CHD. 2 The authors screened 270 individuals with non-syndromic CHD for the GATA6 gene by direct sequencing, and identified a missense mutation (S184N) in three individuals, one with tetralogy of Fallot and the others with atrial septal defect. Although the incomplete penetrance of the phenotype by this mutation was observed, the mutation was not found in 500 ethnically matched healthy controls. And their subsequent biological analysis revealed the decreased transcriptional activity of GATA6 with the S184N mutation for the gene regulation of several important cardiac factors, suggesting that the GATA6 S184N mutation may have an important role in the pathogenesis of CHD.The first identification of disease-associated mutations of GATA6 in CHD was originally reported by us. 3 We screened mutations of cardiac transcription factors in patients with selected non-syndromic CHD, namely persistent truncus arteriosus, representing the most severe cardiac outflow tract (OFT) defects. Two different GATA6 mutations were identified in two probands, but not in 182 unrelated controls with no CHD. Our subsequent biological analyses revealed that genes encoding the neurovascular guiding molecule semaphorin 3C and its receptor plexin A2 were directly regulated by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggested that the expression of semaphorin 3C and plexin A2 in the OFT was dependent on GATA transcription factors during the heart development. Together, our data implicate mutations in GATA6 as novel genetic causes of CHD involving the OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling. Another recent study by Maitra et al. showed two novel sequence variations in GATA6 (A178V and L198V) from the screening of 310 individuals with CHD. 4 These variants were identified in two individuals, one with tetralogy of Fallot and another with atrioventricular septal defect, but not in 288 ethnically matched healthy controls. Biochemical analysis demonstrated that the GATA6 A178V mutant protein resulted in increased transactivation ability for cardiac genes compared with the wildtype. Our first report and subsequent reports by Maitra et al. 4 and Lin et al. 2 in this issue...

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“…7,10 The second heart field is composed of progenitor cells from the medial splanchnic mesoderm adjacent to the pharyngeal endoderm and is the source of the outflow tract (conus cordis and truncus arteriosus) as well as the majority of the right ventricle and atria/ venous pole of the heart. 9,10 The second heart field forms the endothelium, the inner sheath of the cardiac tube and compartments of the heart as they develop.…”

Section: Cardiac Progenitor Cellsmentioning

confidence: 99%

“…Another subset undergoes epithelial-to-mesenchymal transformation and form interstitial fibroblasts and coronary blood vessels including vascular smooth muscle cells and endothelium. 7 A few of the proepicardial cell precursors differentiate into myocytes located in the muscular ventricular septum and atria. 5,26 …”

Section: Cardiac Progenitor Cellsmentioning

confidence: 99%

Cardiac Embryology and Molecular Mechanisms of Congenital Heart Disease: A Primer for Anesthesiologists

Kloesel

DiNardo

Body

2016

Anesthesia &Amp; Analgesia

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Congenital heart disease is diagnosed in 0.4% to 5% of live births and presents unique challenges to the pediatric anesthesiologist. Furthermore, advances in surgical management have led to improved survival of those patients, and many adult anesthesiologists now frequently take care of adolescents and adults who have previously undergone surgery to correct or palliate congenital heart lesions. Knowledge of abnormal heart development on the molecular and genetic level extends and improves the anesthesiologist's understanding of congenital heart disease. In this paper we aim to review current knowledge pertaining to genetic alterations and their cellular effects that are involved in the formation of congenital heart defects. Given that congenital heart disease can currently only occasionally be traced to a single genetic mutation, we highlight some of the difficulties that researchers face when trying to identify specific steps in the pathogenetic development of heart lesions.

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Molecular embryology for an understanding of congenital heart diseases

Cited by 16 publications

References 30 publications

Bmp signaling repressesVegfato promote outflow tract cushion development

Bmp signaling repressesVegfato promote outflow tract cushion development

GATA transcription factors in congenital heart defects: A Commentary on a novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

Cardiac Embryology and Molecular Mechanisms of Congenital Heart Disease: A Primer for Anesthesiologists

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